Gout is a common and excruciatingly painful inflammatory arthritis associated with hyperuricemia. Emerging evidence suggests that gout may increase the risk of myocardial infarction, diabetes, and premature death. In addition to various dietary and life-style risk factors for gout, substantial genetic predisposition of gout has been recognized. A family history of gout increases an individual's risk of developing gout nine-fold and a positive family history has been reported as high as 80% among gout patients. Serum uric acid levels, the precursor of gout, also show a high degree of heritability (0.63). However, the genetic factors responsible for this strong predisposition remain unknown. This project will build on and extend our previous efforts (examining environmental risk factors for gout) by allowing us to study the relation of gout and serum uric acid to specific genetic factors and gene-environment interactions. We will take advantage of data collected in three large cohort studies: Nurses' Health Study (NHS) I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health Professionals Follow-up Study (HPFS) (n=51,000 men). We will perform a two-stage genome-wide association (GWA) study to identify genes that affect the risk of gout. In Stage 1, we will perform a GWA study examining 550,000 SNPs in 1,200 participants with gout and 1,200 matched controls. We will release these results with a genome-wide significance level of 10-7 and select the top 1% for subsequent genotyping. In Stage 2, we will genotype these top 1% genes (and other candidate genes and validation markers) using 25k custom chips in an independent sample of 1,200 gout cases and 1,200 controls from our cohorts. We will perform a two-stage joint analysis, which achieves efficiency without sacrificing power. Next, we will exam gene- environment interactions between the top 50 SNPs from the joint analysis and key environmental risk factors (purine-rich food, alcohol, and adiposity) in all 4,800 participants. We will also identify genes associated with hyperuricemia as a secondary outcome. During the proposed 4-year study period, we will continue to confirm incident cases of gout according to the American College of Rheumatology gout criteria. The significance and strengths of the current proposal include: 1) importance of the study topic (i.e. a key risk factor [genes] for a common, painful, rheumatic condition [gout]), 2) comprehensive investigative approach, 3) our extensive ongoing experience in gout research, 4) an ideal environment for a genetic epidemiology study (i.e. Channing laboratory and Harvard School of Public Health), 5) well-validated, prospectively collected dietary and other environmental exposure data, 6) large sample size providing high precision and power for the proposed estimates, 7) prospective incident outcome analysis, and 8) cost- efficient study design using well-established, validated data. This study will fill the major gaps in our knowledge on the genetic risk factors for gout, which may lead to new approaches to treatment. Public Health Relevance: Gout is a common and excruciatingly painful inflammatory arthritis associated with elevated uric acid levels. A strong genetic predisposition to gout has been recognized for centuries, but the mechanisms involved remain unknown. This project will build on and extend our previous efforts (examining environmental risk factors for developing gout) by allowing us to study the relation of gout to specific genetic factors. We will take advantage of prospective data and DNA samples collected in four large cohort studies: Nurses' Health Study (NHS) I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health Professionals Follow-up Study (HPFS) (n=51,000 men). [unreadable] [unreadable] [unreadable]